An autophagy assay reveals the ESCRT-III component CHMP2A as a regulator of phagophore closure

Yoshinori Takahashi (), Haiyan He, Zhenyuan Tang, Tatsuya Hattori, Ying Liu, Megan M. Young, Jacob M. Serfass, Longgui Chen, Melat Gebru, Chong Chen, Carson A. Wills, Jennifer M. Atkinson, Han Chen, Thomas Abraham and Hong-Gang Wang ()
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Yoshinori Takahashi: Penn State College of Medicine
Haiyan He: Penn State College of Medicine
Zhenyuan Tang: Penn State College of Medicine
Tatsuya Hattori: Penn State College of Medicine
Ying Liu: Penn State College of Medicine
Megan M. Young: Penn State College of Medicine
Jacob M. Serfass: Penn State College of Medicine
Longgui Chen: Penn State College of Medicine
Melat Gebru: Penn State College of Medicine
Chong Chen: Penn State College of Medicine
Carson A. Wills: Penn State College of Medicine
Jennifer M. Atkinson: Penn State College of Medicine
Han Chen: Penn State College of Medicine
Thomas Abraham: Penn State College of Medicine
Hong-Gang Wang: Penn State College of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract The mechanism of phagophore closure remains unclear due to technical limitations in distinguishing unclosed and closed autophagosomal membranes. Here, we report the HaloTag-LC3 autophagosome completion assay that specifically detects phagophores, nascent autophagosomes, and mature autophagic structures. Using this assay, we identify the endosomal sorting complexes required for transport (ESCRT)-III component CHMP2A as a critical regulator of phagophore closure. During autophagy, CHMP2A translocates to the phagophore and regulates the separation of the inner and outer autophagosomal membranes to form double-membrane autophagosomes. Consistently, inhibition of the AAA-ATPase VPS4 activity impairs autophagosome completion. The ESCRT-mediated membrane abscission appears to be a critical step in forming functional autolysosomes by preventing mislocalization of lysosome-associated membrane glycoprotein 1 to the inner autophagosomal membrane. Collectively, our work reveals a function for the ESCRT machinery in the final step of autophagosome formation and provides a useful tool for quantitative analysis of autophagosome biogenesis and maturation.

Date: 2018
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DOI: 10.1038/s41467-018-05254-w

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